Markku Mäki

Deamidated gliadin peptides form epitopes that transglutaminase antibodies recognize.

Objective: Deamidated gliadin peptides are efficient antigens in diagnostic tests for celiac disease, and results correlate better with transglutaminase 2–based assays than those with native gliadin. We investigated whether deamidated gliadin antigens are structurally similar to transglutaminase 2 or could mimic transglutaminase epitopes. Patients and Methods: Serum samples from 74 celiac and 65 control patients, and 13 different transglutaminase 2–specific monoclonal mouse antibodies were investigated for their binding to commercially available deamidated gliadin peptides using enzyme-linked immunosorbent assay, competition studies, and molecular modelling. Results: The enzyme-linked immunosorbent assay with deamidated gliadin peptides had 100% sensitivity and 98.5% specificity in patients. Deamidated gliadin epitopes also were recognized by 3 transglutaminase-specific monoclonal antibodies, and antibodies affinity-purified with deamidated gliadin peptides from celiac patient sera reacted with transglutaminase but did not show endomysial binding. The binding of the monoclonal antibodies to deamidated gliadin was inhibited dose dependently by full-length recombinant human transglutaminase, its fragments containing the binding sites of these monoclonal antibodies, or by celiac patient antibodies. Deamidated gliadin peptides decreased the binding of transglutaminase-specific monoclonal antibodies to transglutaminase. Three different cross-reacting transglutaminase epitopes were found, of which 2 are located in the C-terminal domain and 1 is conformational. The binding of celiac serum samples to deamidated gliadin peptides could not be abolished by transglutaminase or by any of the transglutaminase-specific monoclonals, indicating that celiac sera also contain additional antibodies to gliadin epitopes different from transglutaminase. Conclusions: Certain deamidated gliadin–derived peptides and transglutaminase 2 epitopes have similar 3-dimensional appearance. This homology may contribute to the induction of transglutaminase autoantibodies by molecular mimicry.

Celiac Disease Autoimmunity and Hip Fracture Risk: Findings from a Prospective Cohort Study

The impact of celiac disease autoimmunity on bone health is unclear. We investigated the associations of seropositivity for tissue transglutaminase antibodies (tTGA) and endomysial antibodies (EMA) with incident hip fractures using data from a prospective cohort study, Mini‐Finland Health Survey. Baseline serum samples, taken in 1978–80, were tested for tTGA and EMA. Incident hip fractures up to the year 2011 were ascertained from a national hospitalization register. Associations between seropositivity and hip fractures were modeled using Cox proportional hazards regression adjusted for age, sex, body mass index, vitamin D, gamma‐glutamyl transferase, smoking, and self‐rated health. Our analyses were based on 6919 men and women who had no record of celiac disease or hip fracture before the study baseline. A total of 382 individuals had a hip fracture during a median follow‐up of 30 years. Compared with the tTGA‐negative individuals (n = 6350), tTGA‐positive participants (n = 569; with hip fracture, n = 51) had a higher risk of hip fractures (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.17, 2.14). The findings were similar for another tTGA test (n 200; with hip fracture, n = 26; HR = 2.23, 95% CI 1.49, 3.34). We found no evidence for an association between EMA positivity and hip fracture risk (HR = 0.92, 95% CI 0.34, 2.47; n = 74; with hip fracture, n = 4). In our prospective population‐based study of Finnish adults, seropositivity for tTGA was associated with an increased hip fracture risk.